Cocaine Impact on Neural Plasticity: Modulation by Genetic Vulnerability &Social Stress. This project tests the hypothesis that a major impact of cocaine on the brain is to alter the expression of genes relating to neural plasticity in reward and stress-related circuits, and to affect hippocampal morphology and neurogenesis. The proposed studies will use two lines of animals selectively bred for twelve generations for the novelty-seeking trait (high responders-HR versus low responders-LR). This trait relates to general reactivity to the environment including "novelty-seeking" behavior, and predicts initial likelihood to self-administer drugs. The selectively bred animals will be exposed to cocaine, followed by various periods of abstinence using two methods of cocaine delivery: Self-Administration and Experimenter Administration. They will be tested either under control conditions or following a social stressor. The differential impact of these manipulations will be assessed by measuring altered expression of a panel of growth factor genes, stress genes and synaptic plasticity genes in two regions of the hippocampus (HC) and in the core and shell of the nucleus accumbens (NAcc). The choice of the target genes was based on a combination of existing literature findings and our own data based on microarray profiling after social stress and drug self-administration. Associated changes in hippocampal morphology and neurogenesis will be studied at each of'these phases. Of particular interest will be those drug-related genes whose alterations are sustained long after drug administration has ceased, as they may point to mechanisms of enduring effects of substance abuse that would lead to relapse. Promising genes will be functionally characterized by protein analysis and pharmacological administration of agonists, antagonists or analogues to assess their potential role in modulating the sequelae of exposure to cocaine in animals with differing susceptibility to the drug. This work should lead to new discoveries regarding the molecular mechanisms of addiction and provide novel targets for its treatment.